1. Field of the Invention
The present invention is directed to a method of treating bacterial infections caused by a bacteria selected from the group consisting of Streptococcus pneumoniae, Haemophilus influenza, Hemophilus parainfluenza, Burkholderia (Pseudomonas) cepacia and a mixture thereof using an oligosaccharide, as well as a pharmaceutical composition containing same.
2. Discussion of the Background
S. pneumoniae, H. influenza, H. parainfluenza, and Burkholderia (Pseudomonas) cepacia are pathogenic bacteria associated with respiratory diseases such as pneumonia, bacterial bronchitis, conjunctivitis, sinusitis and otitis media. In each of these conditions, the bacteria colonizes the healthy tissue of the nasopharynx, conjunctiva, lung, bronchi or ear canal, establishing a large enough population to cause the disease. The bacteria adhere to the cell-surfaces, at specific receptor sites for the bacteria.
Conventional therapy has relied on administration of antibiotics, in order to alleviate the bacterial colonization. However, antibiotic therapy is subject to the development of antibiotic resistant strains, (and can ultimately generate "super bacteria") which would not be treatable with known antibiotics. A report issued by the American Society of Microbiology, in May of 1995, indicated that more and more infectious organisms are becoming untreatable with antibiotics and that steps must be taken to reverse this trend before a public health crisis occurs.
Researchers have studied the interactions of pathogenic bacteria with tissue receptors, responsible for adherence, and have identified specific carbohydrate sequences which can inhibit bacterial adherence.
Krivan et al U.S. Pat. No. 5,386,027, report binding inhibition of specific "opportunistic pathogenic bacteria", which are associated with respiratory tract infections, with compounds containing either an internal or terminal GalNAc.beta.1-4-Gal.beta.1-4-Glc sequence. The specific pulmonary pathogenic bacteria for which binding inhibition are reported are Pseudomonas aeruginosa, Haemophilus influenza, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae and Escherichia coli. The reference postulates that ganglioside GM1 is present in substantial amounts in human lung tissue and that pulmonary pathogenic bacteria require at least a terminal or internal GalNAc.beta.1-4-Gal, which is unsubstituted with sialyl residues.
Andersson et al J. Exp. Med. (1983), v. 158, p. 559-570, report binding inhibition studies on Streptococcus pneumoniae, and identify a disaccharide GlcNAc .beta.1-3-Gal.beta. as a specific glycoconjugate receptor. The reference reports that compound 3, NeuAc.alpha.2-3Gal.beta.1-4-GlcNAc.beta.1-3-Gal.beta.1-4-Glc-Cer had no effect at binding inhibition (page 564, first sentence under Table IV).
Rosenstein et al, Infection and Immunity (1992), vol. 60, no. 12, 5078-5084, report binding specificities for Pseudomonas aeruginosa M35 and Escherichia coli C600, isolated from cystic fibrosis patients for various oligosaccharide structures. Gal.beta.1-4-GlcNAc.beta.-3-Gal.beta.1-4-Glc was reported to have high binding activity while NeuAc.alpha.2-6-Gal.beta.1-4-GlcNAc.beta.1-3-Gal.beta.1-4-Glc showed no activity.
Ramphal et al, Infection and Immunity (1991) vol. 59, no. 2, p. 700-704, report binding inhibition studies for Pseudomonas aeruginosa to Type 1 (Gal.beta.1-3-GlcNAc) and Type 2 (Gal.beta.1-4GlcNAc) disaccharides. NeuAc.alpha.2-6-Gal.beta.1-4-GlcNAc.beta.1-3-Gal.beta.1-4-Glc is reported to have no activity in the direct adhesion assay.
Ginsburg et al U.S. Pat. No. 5,225,330 report a diagnostic device for absorbing microorganisms, using specific carbohydrate receptor sequences. The reference reports no activity for sialylparagoboside in binding inhibition of Mycoplasma pneumoniae (Table I, col. 11) but reports Escherichia coli inhibition of N-glycolylsialoparagloboside.
Feizi et al Biochemistry, 1994, 33, 6342-6349, report that NeuAc.alpha.2-6-Gal.beta.1-4-GlcNAc.beta.1-3-Gal.beta.1-4-Glc is not bound or is only negligibly bound by immunoglobulin E-binding protein, while NeuAc.alpha.2-3-Gal.beta.1-3-GlcNAc.beta.1-3-Gal.beta.1-4-Glc is strongly bound by this protein.
Magnani et al WO92/18610 report the use of sialyl-Lea.sup.a (Neu5Ac.alpha.2-3-Gal.beta.1-3[Fuc.alpha.1-4]GlcNAc) and sialyl-Le.sup.x (Neu5Aca2-3-Gal.beta.1-4[Fuc.alpha.1-3]GlcNAc) in inhibiting binding of malignant cells to endothelial cells both in vivo and in vitro.
Andersson et al J. of Infectious Diseases (1986), vol. 153, no. 2, 232-237, report that fractions of human milk inhibited the attachment of Streptococcus pneumoniae and Haemophilus influenaze to human pharyngeal or buccal epithelial cells.
Accordingly, new methods of treating bacterial infections of a bacteria selected from the group consisting of Streptococcus pneumoniae, Haemophilus influenza, Hemophilus parainfluenza, Burkholderia (Pseudomonas) cepacia and a mixture thereof, are being sought, which have a lower probability of generating antibiotic resistant strains. Anti-adhesion compounds are potentially useful candidates in this search.